This revised proposal describes a 5 year mentored research project designed to transition the applicant into an independent translational scientist. During the project period, the Principal Investigator (P.l.) will devote efforts towards broadening his knowledge base and technical skills as necessary to ultimately supervise a successful laboratory based program in cancer biology. The development of the P.l. will be fostered by ongoing mentorship by an established expert in the field of cancer biology, Dr. Neal Rosen, at an institution renowned for training clinician scientists in cancer research. Memorial Sloan-Kettering Cancer Center. The focus of the applicant's research is the study of the functions of activated PI3K-AKT signaling in breast cancer. This pathway is activated in many breast cancers including those characterized by HER2 amplification. HER2/ErbB2 primarily activates the PI3K-AKT pathway by dimerizing with the HER3/ErbB3 receptor. The applicant now reports that activation of the PI3K-AKT pathway generates inhibitory signals against the ErbB3 receptor. This proposal is aimed at elucidating the mechanisms and consequences of these inhibitory signals in tumor formation and maintenance. The proposal will test three hypotheses: (1) The PI3K-AKT pathway regulates a discrete set of signals that control the expression of the ErbB3 receptor. (2) The regulation of ErbB3 expression by the PI3K-AKT pathway can impede tumorigenesis but is ultimately overcome in invasive cancers. (3) Therapeutic strategies that incorporate inhibition of ErbB3 induction will be more effective than inhibition of HER2 or AKT alone. In Aim 1, we will use pharmacologic and genetic manipulations to determine both the context and mechanism of PI3K-AKT regulation of ErbB3 expression. In Aim 2, we will determine the effect of deregulated ErbB3 expression upon tumor formation and evaluate whether this takes place in human tumor samples. In Aim 3, we will evaluate the efficacy of combined inhibition of AKT and HER1/2 or selective inhibition of ErbB3 in models of HER2 amplified breast cancer. The overall goal of these studies is to detail the full consequences of activated PI3K-AKT signaling in breast cancer and to develop novel strategies that target dysregulated AKT as therapeutic approaches.